ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1576C>T (p.Gln526Ter)

gnomAD frequency: 0.00002  dbSNP: rs768530578
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001242116 SCV001415183 pathogenic not provided 2024-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln526*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs768530578, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 967250). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002402766 SCV002710062 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-09-03 criteria provided, single submitter clinical testing The p.Q526* variant (also known as c.1576C>T), located in coding exon 14 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1576. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely.
Fulgent Genetics, Fulgent Genetics RCV005029823 SCV005656758 pathogenic Noonan syndrome 2; LZTR1-related schwannomatosis; Noonan syndrome 10 2024-02-26 criteria provided, single submitter clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis RCV005054351 SCV005688750 pathogenic Noonan syndrome 2 2023-11-27 criteria provided, single submitter clinical testing The LZTR1 c.1576C>T (p.Gln526Ter) variant has been reported in the literature in a single individual with schwannomatosis, but no additional information was reported (Louvrier C et al., PMID: 29409008). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is only observed on 5/234,626 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

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